Plasma cells are the major immunoglobulin-producing cells in humans. While a great deal has been learned in recent years on the development of the B cell lymphoid lineage that gives rise to plasma cells, there has been very little molecular insight into the process of plasma cell development and maintenance. For this reason there are at present few, if any, useful pharmacological tools for manipulating plasma cell development and function. It is highly likely that drugs that would interfere with plasma cell development and function would be useful in treating human diseases caused by pathogenic immunoglobulins (that are produced by plasma cells). Such drugs would also be useful in treating diseases such as Multiple Myeloma, a common human cancer in which plasma cells proliferate abnormally.
XBP-1 (X-box binder protein 1), which encodes a transcription factor, has been described as playing a role in plasma cell development, as reported by Reimold et al., “Plasma Cell Differentiation Requires the Transcription Factor XBP-1,” Nature 412:300-307 (2001). In that study, mice lacking the XBP-1 gene were unable to develop plasma cells and had impaired immunoglobulin secretion. Because of the apparent crucial role of XBP-1 in plasma cell development and function, Reimold et al. suggested that a drug that would prevent XBP-1 action or expression would be useful. However, because it is very difficult to inhibit a transcription factor (such as XBP-1), it is not likely that XBP-1 would be a good drug target for developing treatments of diseases associated with plasma cell function. Thus, rather than directly targeting XBP-1 as a means for inhibiting plasma cell development, targeting other factors in the XBP-1 pathway may be useful in developing drugs or other treatments for diseases associated with plasma cell development.
IRE1 is a stress-activated endonuclease that resides in the endoplasmic reticulum. The processing of XBP-1 by IRE1 has been previously reported (Shen et al., “Complementary Signaling Pathways Regulate the Unfolded Protein Response and are Required for C. elegans Development,” Cell 107:893-903 (2001), Yoshida et al., “XBP1 mRNA is Induced by ATF6 and Spliced by IREI in Response to ER Stress to Produce a Highly Active Transcription Factor,” Cell 107:881-891 (2001), and Calfon et al., “IRE1 Couples Endoplasmic Reticulum Load to Secretory Capacity by Processing the XBP-1 mRNA,” Nature 415:92-96 (2002)). However, knowledge in the art of how to develop treatments for plasma cell associated diseases by targeting the XBP-1 pathway, and particularly IRE1, is not well developed. In particular, it would be important to the medical community to have assays that screen for compounds that can be developed into drugs for inhibiting plasma cell development and function. Currently, the only drugs known to inhibit abnormal plasma cells are proteasome inhibitors that are in clinical trials (Adams, “Proteasome Inhibition in Cancer: Development of PS-341,” Semin. Oncol. 28: 613-9 (2001)).
The present invention is directed to overcoming these and other deficiencies in the art.